LRRC57/RABIN is a presynaptic inhibitor of Rab GTPases in glutamatergic neurons

Abstract

Synaptic vesicle cycling, if not properly constrained, can result in excessive neurotransmitter release and subsequent neural pathology. Rab GTPases orchestrate synaptic vesicle trafficking through GTP-dependent interactions with effector proteins, but the restraining mechanism of these interactions is unknown. Here we identify LRRC57 (or RABIN for RAB INhibitor), a conserved brain-enriched protein in glutamatergic synapses that binds multiple GTP-loaded synaptic Rabs and competitively blocks access to their effectors. Loss of Rabin increased glutamate release, expanded vesicle pools, accelerated vesicle turnover, and produced circuit hyperexcitability with epileptiform activity, which was mitigated by an antiepileptic agent that targets presynaptic function. Conversely, overexpression of the Rabin gene suppressed neurotransmitter release and protected against induced seizures and persistent epileptiform discharges. Together, these findings define a noncanonical decoy-effector mechanism that constrains presynaptic Rab signaling to preserve excitatory circuit stability.

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BibTeX RIS

BibTeX

@misc{garic2026lrrc57rabin,
  title = {{LRRC57/RABIN is a presynaptic inhibitor of Rab GTPases in glutamatergic neurons}},
  author = {D. Garic and J. G. Murphy and B. J. W. Teubner and C. M. Davenport and C. D. Shreffler and L. J. Janke and W. J. Cho and Z. Wu and M. McReynolds and S. Phasuk and J. Y. Fu and D. A. Lewis and T. Confer and J. Klein and M. Johnson and C. G. Robinson and S. M. Pruett-Miller and R. J. Heath and J. Peng and J. D. Vevea and S. S. Zakharenko},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.05.743108},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.05.743108v2},
  note = {CC BY-ND},
}

RIS

TY  - UNPB
TI  - LRRC57/RABIN is a presynaptic inhibitor of Rab GTPases in glutamatergic neurons
AU  - D. Garic
AU  - J. G. Murphy
AU  - B. J. W. Teubner
AU  - C. M. Davenport
AU  - C. D. Shreffler
AU  - L. J. Janke
AU  - W. J. Cho
AU  - Z. Wu
AU  - M. McReynolds
AU  - S. Phasuk
AU  - J. Y. Fu
AU  - D. A. Lewis
AU  - T. Confer
AU  - J. Klein
AU  - M. Johnson
AU  - C. G. Robinson
AU  - S. M. Pruett-Miller
AU  - R. J. Heath
AU  - J. Peng
AU  - J. D. Vevea
AU  - S. S. Zakharenko
PY  - 2026
DA  - 2026/08/05
PB  - bioRxiv
DO  - 10.64898/2026.08.05.743108
UR  - https://www.biorxiv.org/content/10.64898/2026.08.05.743108v2
AB  - Synaptic vesicle cycling, if not properly constrained, can result in excessive neurotransmitter release and subsequent neural pathology. Rab GTPases orchestrate synaptic vesicle trafficking through GTP-dependent interactions with effector proteins, but the restraining mechanism of these interactions is unknown. Here we identify LRRC57 (or RABIN for RAB INhibitor), a conserved brain-enriched protein in glutamatergic synapses that binds multiple GTP-loaded synaptic Rabs and competitively blocks access to their effectors. Loss of Rabin increased glutamate release, expanded vesicle pools, accelerated vesicle turnover, and produced circuit hyperexcitability with epileptiform activity, which was mitigated by an antiepileptic agent that targets presynaptic function. Conversely, overexpression of the Rabin gene suppressed neurotransmitter release and protected against induced seizures and persistent epileptiform discharges. Together, these findings define a noncanonical decoy-effector mechanism that constrains presynaptic Rab signaling to preserve excitatory circuit stability.
ER  -

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